Acyl derivatives of germinal gland hormone preparations of high activity, and a method of producing the same



Patented Apr. 28, 1942 ACYL DERIVATIVES OF GERIYHNAL GLAND HORMONEPREPARATIONS OF HIGH AC- TIVITY, AND A METHOD OF PRODUCING THE SAMEUNITED STATES PATENT OFFICE N Drawing.

Original application February 21,

1935, Serial No. 7,604. Divided and this application October 9, 1936,Serial No. 104,848. In Germany February 22, 1934 (01. zoo-397.5)

8 Claims.

This invention relates to acyl derivatives of germinal gland hormonepreparations of high physiological activity and more particularly toacyl derivatives of compounds of an activity simmethod of producing thesame.

ruary 21, 1935.

in order to attain a lasting effect.

hormone deposit in the organism.

duction of these esters.

the method used.

of the monoacyl derivative.

groups can be acylated.

pound. The acylation may be carried out by using the acid anhydride orthe acid chloride or the acid itself as acylating agents in the presenceor absence of catalysts or in any other known manner.

A further method for arriving at these esters ilar to that of the malesex hormones, and a consists in the hydrogenation of the esters of Thepresent application is a division of our the r spond p n u ds, su acopending application Serial No. 7,604, filed Febthe alkyl derivativesof the follicle hormones produced, for example, by reacting an ethersolution Hormone alcohols such as are obtained, for 10 0f folliclehormone With alkyl magnesium o example, by the reaction ofketo-containing satufOllOWed by hydrolysis d extraction W ether, ratedgerminal gland hormones t organoas described in application Serial No.748,664 eta lic halides, followed by hydrolysis, as 6.6- above referredto, or the esters of the follicle scribed in application Serial No.748,664 of Friedhormone hydrate a d s la p du ts. The hyri h Hildebrandtare distinguished by their drogenation is interrupted when the aromaticphysiological activity being similar to that of the nucleus iscompletely saturateds od m l germinal gland hormones. s compounds, hasthe advantage that it is possible with its help however, are so quicklyeliminated from the orto arrive at monoacyl compounds of said satuganismthat frequent applications are necessary rated polyalcohols- Thus, thereis produced, for instance, by catalytic hydrogenation of the Now we havediscovered that the esters of the methyldiol 0f the formula (319112602,acylated hormones or hormone-like substances have a on the PhenolichydrOXy p, the -a O Y more lasting action and the disadvantage abovehexahydro methyldioL m ti d can accordingly be remedied by using, Theproduction of this type of partially esteriin t d of t alcohols or ketoalcohals, their fied polyalcohols is therapeutically of interest t hi honly gradually are eliminated from and, besides, these compounds areimportant as r th organism The esters for so to speak, a intermediateproducts for the production of compounds of the character of germinalgland hor- Knowh methods may be empbyed for the mones. In order to carryout the hydrogenation Thus, f r instance, the catalytically activatedhydrogen is used in the alcohols may be reacted with acid chlorides inknown I t presence of inorganic or organic bases of Instead of usingcatalytically activated hydrocourse, other acylation methods may also beused. gen as hydmgenating agent, ot r re uc When dihydroxy compounds areemployed, monoagents capable of hydmgenating a bon-to-caror diacylderivatives are formed, depending on 85 hon double bonds may be d. Themonoacyl compounds obtained thereby may be converted For instance, bycarrying out the reaction in a mto the colfresponding diacyl pounds byfursolvent wherein the primarily formed monoacyl the!acyla'tlolflderivative is soluble only with dimculty, the The follow 1ngexamples serve to illustrate the acylation can be interrupted after theformation 40 ig s gif Wlthout, however, ng the same On carrying out theacylation in a solvent Efllllmple 1 wherein the monoas well as thediacylation 1 of the 3-aoetoxy methyldiol produced by Products e pt n8011111011, both hydroXy acylation, according to Schotten-Baumann, of n45137116 Grignard pound obtained by reacting The terms aoy at on p s andy a s methyl magnesium iodide with crystallized r agent as usedhereinafter in the specification licle hormone in ether solution,followed Whyand the claims include the known processes and drolysis withHCl, dilution with water and exagents for introducing an acyl group intoa comtraction with ether, as described in the above mentionedapplication Serial No. 748,664, is hydrogenated in glacial acetic acidsolution with hydrogen in the presence of platinum oxide catalystaccording to Adams-Shriner at room temperature while shaking, until thebenzene nucleus is completely saturated. The reaction solution, freedfrom the catalyst, is evaporated in a vacuum to dryness, whereby theS-acetoxy hexahydro methyldiol is obtained.

Example 2 1 g. of follicle hormone hydrate acetylated on the phenolichydroxy group, is dissolved in 200 cc. of ethyl alcohol and then treatedwith hydrogen in the presence of 1 g. of a previously reduced nickelcatalyst, at 180 C. and 100 atmospheres in a stirring autoclave. .Aftercomplete hydrogenation the reaction solution, freed from the catalyst,is evaporatedto dryness. As'residue there remains a viscous resin.

The following structural formulas serve to illustrate the compounds usedas starting materials and obtained by the invention:

Starting material I Reaction product I M hydrogenation I H l H 30wherein X is an alkyl or aryl group and R an acyl p- Starting material11 Reaction product II H OH wherein R represents an acyl group, to theaction of a reducing agent capable of hydrogenating the benzene nucleusin the molecule of said starting material into a hydro-aromatic nucleus,stopping the hydrogenation when the benzene nucleus has beenhydrogenated, and recovering a compound of the formula 2.Acylderivatives of cyclopentano tetradecahydro phenanthrene compounds ofthe following structural formula CHI wherein X is a member of the groupconsisting of hydrogen, alkyl and aryl radicals, andR,R are the same ordifferent acyl groups; said derivatives having a physiological activitysimilar to that of'the male sex hormones.

3. Acyl derivatives of cyclopentano tetradecahydro phenanthrenecompoundsof the following structural formula H OR wherein R, R. are the same'or'different acyl groups; said derivatives having a physiologicalactivity similar to that of the male sex hormones.

4. Acyl derivatives of cyclopentano tetradecahydro phenanthrene'comoundsof the following structural formula wherein .X is a hydrocarbonradical, and R,,-ZR are thesame or difierentracyl groups;saidfierivatives having a physiological activity. similar to that of themale sex hormones.

5. Acyl= derivatives :of .cyfllopentano-tetradecw hydro phenanthrenecompounds of the following structural formula .CHI

, I OH wherein X is an alkyl radical, and R, R are the same or difierentacyl groups; said derivatives having a physiological activity similar tothat of the male sex hormones.

6. A method of producing acyl derivatives of germinal gland hormonepreparations, comprising subjecting an acyl derivative of the followingstructural formula x OH H I OH wherein X represents a member of thegroup consisting of hydrogen, alkyl, and aryl radicals, and R is an acylgroup, to the action of a reducing agent capable of hydrogenating thebenzene nucleus into a hydro-aromatic nucleus, and stopping the reactionwhen the benzene nucleus has been hydrogenated.

'7. A method according to claim 6, wherein the hydrogenated mono-acylderivative is converted into the corresponding poly-acyl compound byfurther acylation.

8. Acyl derivatives of cyclopentano tetradecahydro phenanthrenecompounds of the following structural formula X OB wherein X is ahydrocarbon radical, R is an acyl group, and R is a member of the groupconsisting of hydrogen and acyl; said derivatives having a physiologicalactivity similar to that of the male sex hormones.

WALTER SCHOEILER. FRIEDRICH HILDEBRANDT. ERWIN SCHWENK.

